The mitochondrial genome is highly specialized and encodes for proteins essential for energy metabolism and free radical production-pathways that are also critical for carcinogenesis. Until recently, the mitochondrial genome has received little attention in cancer research as prior studies have largely focused on the nuclear genome. The goal of this proposal is to identify germline mitochondrial DNA variants that influence the risks of breast, colorectal and prostate cancer among a diverse population of African American, Japanese American, Native Hawaiian, Latino and White men and women. We propose in Aim 1 to characterize the genetic diversity of the mitochondrial genome among African Americans, Japanese Americans, Native Hawaiians, Latinos and Whites. We will abstract sequencing data for African Americans, Japanese Americans, Latinos, and Whites from public mtDNA databases, in parallel with sequencing Native Hawaiians (225 controls), a group that is not represented in public resources. Next, we will genotype mtDNA variants identified from sequencing efforts in an independent multiethnic panel of 375 individuals for validation. This work will provide a multiethnic catalog of common mtDNA variation (MAF > 5%). Aim 2 will test the association between common genetic variation in the mtDNA and risks of breast, prostate and colorectal cancer. Based on our compiled catalog of common mtDNA variants, tag SNPs and SNPs representing common haplogroups will be selected (~350 SNPs) and genotyped in our large nested case-control studies of breast (2,586 cases, 2,999 controls), colorectal (2,014 cases, 2,708 controls) and prostate cancer (4,326 cases, 4,714 controls). Our final Aim 3 will evaluate whether mtDNA effects are modified by disease sub-groups (stage, grade, ER+/- breast tumors, colon/rectum tumors), environmental factors related to mitochondrial activity (smoking, BMI, fat, carotenoids, vitamin C, vitamin E, iron, lycopene and selenium) and susceptibility loci for breast, colorectal and/or prostate cancer identified by genome-wide association studies. The strengths of this proposal include: 1) the innovativeness of the research; 2) the multi-disciplinary investigative team, 3) the efficient use of existing resources and 4) the scientific and public health significance, especially in regards to understudied minority populations. The knowledge gained by this study may lead to important insight into the biology of cancers of the breast, colorectal and prostate, and applying this information may improve the prevention, diagnosis and treatment of these common cancers. PUBLIC HEALTH RELEVANCE: For this proposal, we will comprehensively characterize the genetic diversity of the mitochondrial genome among a diverse sample of African American, Japanese American, Native Hawaiian, Latino, and White subjects from the Multiethnic Cohort Study. Using this genetic information, we will investigate whether inherited differences in mitochondrial DNA influence the risk of breast, colorectal, and prostate cancer among nearly 9,000 cancer cases and more than 10,000 controls. In addition, we will evaluate heterogeneity of effects by disease sub-groups, environmental factors and known genetic risk factors.